Process for preparing β-lactam derivative and synthetic intermediate

ABSTRACT

Disclosed is a process for preparing a β-lactam compound represented by the formula: ##STR1## wherein R 1  represents a hydroxy-substituted lower alkyl group or an amino group each of which may be protected; R 2  represents hydrogen atom or an ester residue; X represents a methylene group which may be substituted by a lower alkyl group, sulfur atom or a group represented by the formula: --A--CH 2  -- where A represents sulfur atom, oxygen atom or methylene group; and W represents an active ester residue of hydroxyl group, 
     or a salt thereof, which comprises the steps of treating a 1-aza-3-thia-bicycloalkane compound represented by the formula: ##STR2## wherein R 1 , R 2  and X have the same meanings as defined above, or a salt thereof with a base in the presence of a desulfurizing agent and then reacting the resulting compound with an active esterifying agent of hydroxyl group.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a division of application Ser. No. 08/018,407, filedFeb. 17, 1993, now U.S. Pat. No. 5,414,081.

BACKGROUND OF THE INVENTION

This invention relates to a novel process for preparing a β-lactamderivative useful as a synthetic intermediate of a β-lactam typeantibacterial agent having an antibacterial activity, and relates to asynthetic intermediate of said β-lactam derivative.

As a β-lactam type antibacterial agent, there have been known variouscompounds including a penem or carbapenem series compound such asthienamycin and imipenem, and a cephem, carbacephem or oxacephem seriescompound such as cephalexin.

As to processes for synthesizing these compounds, there have been known,for example, a process which proceeds through an intermediate havingdiphenylphosphoryloxy group at 2-position of a carbapenem skeletondescribed in Japanese Provisional Patent Publication No. 123182/1982 asa process for synthesizing a carbapenem (or penem) series compound, aprocess which proceeds through an intermediate having methanesulfonyloxygroup at 3-position of a cephem skeleton described in JapaneseProvisional Patent Publication No. 21685/1992 as a process forsynthesizing a cephem series compound, and others. However, theconventional processes have problems to be cancelled such as manyoperation steps and complicated reaction operations. Thus, it has beendemanded to develop a process which can prepare a desired antibacterialagent more efficiently.

SUMMARY OF THE INVENTION

An object of the present invention is to provide a novel process forpreparing a β-lactam derivative useful as a synthetic intermediate of aβ-lactam type antibacterial agent and a novel process for preparing aβ-lactam type antibacterial agent using said derivative.

That is, the present invention relates to a novel process for preparinga β-lactam derivative represented by the following formula (I): ##STR3##wherein R¹ represents a hydroxy-substituted lower alkyl group which maybe protected or an amino group which may be protected; R² representshydrogen atom or an ester residue; X represents methylene group, amethylene group substituted by a lower alkyl group, sulfur atom or agroup represented by the formula: --A--CH₂ -- where A represents sulfuratom, oxygen atom or methylene group; and W represents an active esterresidue of hydroxyl group,

which comprises treating a 1-aza-3-thia-bicycloalkane compoundrepresented by the formula (II): ##STR4## wherein the symbols have thesame meanings as defined above, or a salt thereof with a base in thepresence of a desulfurizing agent and then reacting the resultingcompound with an active esterifying agent of hydroxyl group.

DESCRIPTION OF THE EMBODIMENTS

In the following, the present invention is explained in detail.

In the above compound (I), as a specific example of the group R¹, theremay be mentioned a hydroxy-substituted alkyl group having 1 to 6 carbonatoms which may be protected or an amino group which may be protected.

The group X is methylene group, a methylene group substituted by a loweralkyl group such as methyl group and ethyl group, sulfur atom or a grouprepresented by the formula: --A--CH₂ - where A represents sulfur atom,oxygen atom or methylene group. When the group R¹ is ahydroxy-substituted lower alkyl group which may be protected, X isparticularly preferably a methylene group which may be substituted by alower alkyl group or sulfur atom. When the group R¹ is an amino groupwhich may be protected, the group X is particularly preferably a grouprepresented by the formula: --S--CH₂ --, --O--CH₂ -- or --CH₂ CH₂ --.

In the above compound (I), the active ester residue of hydroxyl grouprepresented by W may include, for example, a di-lower alkylphosphorylgroup or diarylphosphoryl group represented by the formula: --P(O)(OR⁰)₂(wherein R⁰ represents a lower alkyl group or an aryl group); asubstituted or unsubstituted lower alkylsulfonyl group such asmethanesulfonyl group and trifluoromethanesulfonyl group; and asubstituted or unsubstituted phenylsulfonyl group such asbenzenesulfonyl group and p-methoxybenzenesulfonyl group.

When the group R¹ of the above compound (I) is a protectedhydroxy-substituted lower alkyl group or a protected amino group, as aprotective group for hydroxy group and amino group, there may be usedany group which can be removed easily by a conventional method such ashydrolysis, acidic treatment and reduction. As such a protective groupfor hydroxy group, there may be mentioned, for example, a loweralkoxycarbonyl group, a halogeno lower alkoxycarbonyl group, asubstituted or unsubstituted phenyl lower alkyl group (e.g. a benzylgroup which may be substituted by nitro group or a lower alkoxy group),a tri-lower alkylsilyl group, and a substituted or unsubstituted phenyllower alkoxycarbonyl group (e.g. a benzyloxycarbonyl group which may besubstituted by nitro group or a lower alkoxy group).

On the other hand, as a protective group for amino group, there may bementioned a lower alkanoyl group, a lower alkoxycarbonyl group, benzoylgroup, benzenesulfonyl group, a phenyl lower alkoxycarbonyl group, atri-lower alkylsilyl group and trityl group.

As an example of the ester residue represented by R², there may bementioned an ester residue which is metabolized and hydrolyzed in aliving body or an ester residue which can be a protective group forcarboxyl group.

The ester residue metabolized and hydrolyzed in a living body mayinclude, for example, a group represented by the formula: --Q--OCOR,--Q--OCO₂ R or --Q--O--R (wherein Q represents a lower alkylene group,and R represents a lower alkyl group, a cycloalkyl group, a loweralkenoyl group, a lower alkoxy lower alkyl group or a lower alkanoyloxylower alkyl group).

On the other hand, the ester residue which can be a protective group forcarboxyl group may include, for example, a lower alkyl group, a loweralkenyl group, a halogeno lower alkyl group, a nitrobenzyl group and alower alkoxybenzhydryl group.

In the above reaction, the compound (II) may be used in the form of asalt, and as a specific example of such a salt, there may be mentionedan alkali metal salt such as a sodium salt or a quaternary ammoniumsalt.

According to the present invention, the 1-aza-3-thia-bi-cycloalkanecompound (II) can be treated with a base in the presence of adesulfurizing agent in a suitable solvent. The base may include, forexample, an alkali metal alkoxide such as potassium tert-butoxide, analkali metal amide such as lithium diisopropylamide, tri-loweralkylamine such as triethylamine, and an aromatic amine such aspyridine. As the desulfurizing agent, there may be mentioned, forexample, a triarylphosphine such as triphenylphosphine, a tri-(loweralkyl)phosphite such as triethyl phosphite, a tri-lower alkylphosphinesuch as triethylphosphine, tris(di-lower alkylamino)phosphite and his(di-lower alkylamino-lower alkyl)phosphite. As the solvent, there may bementioned, for example, toluene, benzene, tetrahydrofuran, diethylether, acetonitrile, methylene chloride, chloroform, dimethylformamideand dimethylsulfoxide. The present reaction is preferably carried undercooling to at room temperature, particularly preferably -40° C. to 0° C.

If necessary, in order to make the present reaction as mentioned aboveproceed more efficiently, a lithium salt such as lithium bromide andlithium perchlorate may be added to the reaction mixture.

The compound obtained by the treatment with a base in the presence of adesulfurizing agent as mentioned above is considered to have thefollowing structure. ##STR5## wherein the symbols have the same meaningsas defined above.

The above resulting compound and an active esterifying agent of hydroxylgroup may be reacted in a suitable solvent. As the active esterifyingagent of hydroxyl group, there may be mentioned, for example, a reactivederivative (e.g. a corresponding acid halide and a corresponding acidanhydride) of a phosphoric acid or sulfonic acid compound including adiaryl phosphate such as diphenyl phosphate; a di-lower alkyl phosphatesuch as diethyl phosphate; a substituted or unsubstituted loweralkanesulfonic acid such as methanesulfonic acid andtrifluoromethanesulfonic acid; and a substituted or unsubstitutedbenzenesulfonic acid such as benzenesulfonic acid andp-methoxybenzenesulfonic acid. As the solvent, there may be used, forexample, ethyl acetate and dioxane in addition to the exemplary solventsto be used for the base treatment of the compound (II). The presentreaction is preferably carried out under cooling to at room temperature,particularly preferably -40° C. to 0° C.

The β-lactam compound (I) thus obtained can be suitably converted into adesired carbapenem (or penem) type antibacterial agent or cephem typeantibacterial agent.

For example, the β-lactam compound (I) can be converted into a β-lactamderivative represented by the formula (IV): ##STR6## wherein R⁴represents an organic group; and R¹, R² and X have the same meanings asdefined above, by subjecting the compound (I) and a mercaptan compoundrepresented by the formula (III):

    R.sup.4 --SH                                               (III)

wherein R⁴ has the same meaning as defined above, or a salt thereof tocondensation reaction.

In the mercaptan compound (III) to be used in the above reaction, as anexample of the organic group represented by R⁴, there may be used anygroup used in a conventionally known carbapenem (or penem) typeantibacterial agent or cephem type antibacterial agent. As a specificexample of such an organic group, there may be mentioned, for example, alower alkyl group such as methyl and ethyl; a cycloalkyl group such ascyclohexyl group; a 6- to 8-membered aryl group such as phenyl group; a4- to 8-membered aliphatic heterocyclic group such as pyrrolidinylgroup; and a 4- to 8-membered aromatic heterocyclic group such aspyridyl group and thiazolyl group. Further, these groups may have one ormore substituent(s), and as such a substituent, there may be mentioned,for example, a lower alkyl group; hydroxyl group; a lower alkoxy group;a mono- or di-lower alkylamino group; mercapto group; a lower alkylthiogroup; amidino group, guanidino group; carbamoyl group; thiocarbamoylgroup; sulfamoyl group; cyano group; carboxyl group; a loweralkoxycarbonyl group; an aralkyloxycarbonyl group; oxo group; a halogenogroup; a cycloalkyl group having 3 to 8 carbon atoms such as cyclohexylgroup; a 6- to 8-membered aryl group such as phenyl group; a 4- to8-membered aliphatic heterocyclic group such as pyrrolidinyl group; anda 4- to 8-membered aromatic heterocyclic group such as pyridyl group andthiazolyl group.

Further, as the mercaptan compound (III), there may be suitably used, inaddition to the compound as described above, a compound represented bythe formula (III-a) described in Japanese Provisional Patent PublicationNo. 279588/1992 filed by the present applicant: ##STR7## wherein R⁵represents hydrogen atom, a lower alkyl group, a lower alkoxy-loweralkyl group or a di-lower alkylamino lower alkyl group.

The above mercaptan compound (III) may be also used in the form of asalt, and as a specific example of such a salt, there may be mentionedan alkali metal salt and a tri-lower alkyl ammonium salt.

The condensation reaction of the compound (I) and the compound (III) maybe carried out in a suitable solvent (e.g. toluene, benzene,acetonitrile, tetrahydrofuran, diethyl ether and ethyl acetate) in thepresence or absence of a base (e.g. a tri-lower alkylamine and a4-di-lower alkylaminopyridine).

In the compound (IV) thus obtained, when the group R¹ is a protectedhydroxy-substituted lower alkyl group or a protected amino group, and/orwhen the group R² is an ester residue, the protective group and/or esterresidue may be removed, if desired, to obtain a compound represented bythe formula (IV-a): ##STR8## wherein R¹¹ represents ahydroxy-substituted lower alkyl group or amino group; and other symbolshave the same meanings as defined above,

or a salt thereof. The protective group or ester residue may be removedaccording to a conventional method.

Further, the above compound (IV) in which R² is hydrogen atom or a saltthereof may be esterified by a conventional method to form a compoundrepresented by the formula (IV-b): ##STR9## wherein R²¹ represents anester residue; and other symbols have the same meanings as definedabove.

Among the compounds (IV) described above, a compound in which the groupR¹ is a hydroxy-substituted lower alkyl group which may be protected,and X is a methylene group which may be substituted by methyl group, orsulfur atom is a compound useful as a carbapenem (or penem) typeantibacterial agent.

On the other hand, a compound in which the group R¹ is an amino groupwhich may be protected, and X is a group represented by the formula:--A--CH₂ -- where A represents sulfur atom, oxygen atom or methylenegroup is a compound useful as a synthetic intermediate of a cephem,oxacephem or carbacephem type antibacterial agent, and said compound canbe converted into a desired cephem type antibacterial agent accordingto, for example, the method described in Japanese Provisional PatentPublication No. 21685/1992.

Among the compounds (IV) described above, a 1-methylcarbapenemderivative represented by the formula (IV-c): ##STR10## wherein R⁶represents hydrogen atom or a protective group for hydroxyl group; andother symbols have the same meanings as defined above,

which can be obtained by subjecting the compound (I) in which R¹ is a1-hydroxyethyl group which may be protected and X is ethylidene groupand the above mercaptan compound (III-a) to condensation reaction is acompound exhibiting various excellent characteristics such as excellentantibacterial activities to various microorganisms includinggram-negative bacteria and gram-positive bacteria and high stability todehydropeptidase I.

In the above process of the present invention, in the starting compound(II), an optical isomer based on an asymmetric carbon atom thereof mayexist. And, when an optically active compound (II) is used as a startingmaterial, a reaction can proceed while maintaining a stereo-structure toconvert the compound (II) into the compound (I) and the compound (IV)without epimerization.

Further, in the reaction of converting the starting compound (II) intothe compound (I) and in the subsequent reaction of converting thecompound (I) into the compound (IV), the compound (I) can be isolatedeasily by a conventional method, but it is also possible to convert thecompound (II) into the compound (IV) in the same reactor withoutisolation.

The starting compound (II) in the present invention is a novel compound,and said compound (II) can be prepared by, for example,

(A) reacting an azetidinone compound represented by the formula (V):##STR11## wherein Z represents a protective group for thiol group; andother symbols have the same meanings as defined above,

with a glyoxylate represented by the formula (VI):

    HOCCO.sub.2 R.sup.2                                        (VI)

wherein R² has the same meaning as defined above, in a suitable solvent(e.g. benzene, chloroform and acetonitrile) under heating, or

(B) reacting the compound (V) with a halogenoglyoxylate represented bythe formula (VII):

    Y.sup.2 OCCO.sub.2 R.sup.2                                 (VII)

wherein y² represents a halogen atom; and R² has the same meaning asdefined above, in a suitable solvent (e.g. dichloromethane,tetrahydrofuran, acetonitrile and chloroform) in the presence of a base(e.g. 2,6-lutidine and pyridine), then reducing the resulting compoundto obtain a compound represented by the formula (VIII): ##STR12##wherein the symbols have the same meanings as defined above, treatingsaid compound (VIII) with a halogenating agent (e.g. thionyl chloride,thionyl bromide, phosphorus tribromide, phosphorus trichloride andmethanesulfonyl chloride) in a suitable solvent (e.g. tetrahydrofuran,chloroform, benzene, acetonitrile and dichloromethane) in the presenceor absence of a base (e.g. pyridine, triethylamine and dimethylaniline)to obtain a compound represented by the formula (IX): ##STR13## whereinY³ represents a halogen atom; and other

symbols have the same meanings as defined above, and further treatingsaid compound (IX) with a base (e.g. a tri-lower alkylamine such astriethylamine, an alkali metal alkoxide such as sodium methoxide and analkali metal amide) in a suitable solvent (e.g. dimethylformamide,dimethylsulfoxide, acetonitrile, tetrahydrofuran, ethyl ether and ethylacetate) to effect cyclization.

The protective group (Z) for thiol group can be removed in thecyclization reaction by treating the compound (IX) with a base, and as aspecific example of such a protective group Z, there may be mentioned,for example, a 2,2-bis(lower alkoxycarbonyl)ethyl group,2,2-dicyanoethyl group, a 2-lower alkoxycarbonylethyl group and2-cyanoethyl group.

Further, the above starting compound (V) can be prepared according to aconventional method, for example, by reacting an azetidinoncarboxylicacid compound represented by the formula (X): ##STR14## wherein thesymbols have the same meanings as defined above, with a compoundrepresented by the formula (XI):

    HS--Z                                                      (XI)

wherein Z has the same meaning as defined above, in a suitable solvent(e.g. acetonitrile) in the presence of a condensing agent (e.g.carbonyldiimidazole and dicyclohexylcarbodiimide), or reacting anacetoxyazetidine compound represented by the formula (XII): ##STR15##wherein Ac represents acetyl group; and R¹ has the same meaning asdefined above,

with a compound represented by the formula (XIII):

    M--X.sup.1 --COSZ                                          (XIII)

wherein M represents hydrogen atom, sodium atom or lithium atom; X¹represents a formula: --S--CH₂ --, --O--CH₂ -- or --CH₂ CH₂ --; and Zhas the same meaning as defined above.

In the present specification and claims, the lower alkyl group, loweralkylene group and lower alkoxy group preferably have 1 to 6 carbonatoms, the lower alkanoyl group and lower alkenyl group preferably have2 to 8 carbon atoms, and further the lower alkenoyl group and cycloalkylgroup preferably have 3 to 8 carbon atoms, respectively.

EXAMPLES

The present invention is described in detail by referring to Examples,but the scope of the invention is not limited by these Examples.

Example 1

(1) In 500 ml of acetonitrile was suspended 26.7 g of(3S,4S)-3-[(R)-1-tert-butyldimethylsilyloxyethyl]-4-[(1R)-1-carboxyethyl]-2-azetidinone,14.6 g of carbonyldiimidazole was added thereto, and the mixture wasstirred at room temperature for 30 minutes. To the reaction mixture wasadded 20.3 g of diethyl mercaptomethylmalonate, and the mixture wasstirred at room temperature for 20 minutes. The solvent was removed fromthe reaction mixture under reduced pressure. After 500 ml of diethylether was added to the residue and the mixture was washed and dried, thesolvent was removed under reduced pressure. The residue was purified bysilica gel column chromatography (solvent; ethyl acetate:n-hexane=1:3)to obtain 33 g of (3S,4S)-3-[(R)-1-tert-butyldimethylsilyloxyethyl]-4-[(1R)-1-{2,2-bis)ethoxycarbonyl)ethylthiocarbonyl}ethyl]-2-azetidinone.

IR (KBr) cm⁻¹ : 3080, 1765, 1735, 1690.

Mass (m/z): 432 (M⁺ -57).

NMR (CDCl₃) δ: 0.07 (s, 6H), 1.15 (d, 3H, J=6.2 Hz), 1.24 (d, 3H, J=6.8Hz), 1.28 (t, 3H, J=7.0 Hz), 2.8 to 3.0 (m, 1H), 3.34 (d, 1H, J=2.4 Hz),3.38 (d, 1H, J=2.4 Hz), 3.8 to 3.9 (m, 1H), 4.2 to 4.3 (m, 5H), 5.62 (brs, 1H).

(2) In 10 ml of benzene were dissolved 1 g of the product obtained aboveand 0.76 g of ethyl glyoxylate, and the mixture was refluxed by heatingfor 2 hours in a reactor equipped with a cooling tube charged with 10 gof Molecular Sieve 4A (trade name, produced by Nacalai tesque INC.).After the reaction mixture was diluted with ethyl acetate, washed anddried, the solvent was removed. The residue was purified by silica gelcolumn chromatography (solvent; ethyl acetate:n-hexane=1:3) to obtain1.0 g of (3S,4S)-3-[(R)-1-tert-butyldimethylsilyloxyethyl]-4 -[(1R)-1-{2,2-bis(ethoxycarbonyl)ethylthiocarbonyl)}ethyl]-1-(1-hydroxy-1-ethoxycarbonylmethyl)-2-azetidinone.

IR (film) cm⁻¹ : 3450, 1770, 1748, 1690.

Mass (m/z): 534 (M⁺ -57).

NMR (CDCl₃) δ: 0.60+0.08 (s+s, 6H), 0.87+0.88 (s+s, 9H), 1.2 to 1.4 (m,15H), 2.9 to 3.1 (m, 2H), 3.3 to 3.4 (m, 2H), 3.62 (t, 1H, J=7.8 Hz),4.0 to 4.4 (m, 9H), 5.30+5.46 (d+d, 1H, J=8.4 Hz).

(3) To 10 ml of tetrahydrofuran solution containing 0.78 g of theproduct obtained above were added dropwise 0.21 ml of pyridine and 0.17ml of thionyl chloride at -50° C., and the mixture was stirred at -50°to -40° C. for 30 minutes. After the reaction mixture was diluted withethyl acetate and washed, an organic layer was collected by separation.The organic layer was dried, and then the solvent was removed. Theresidue[(3S,4S)-3-[(R)-1-tert-butyldimethylsilyloxyethyl]-4-[(1R)-1-{2,2-bis(ethoxycarbonyl)ethylthiocarbonyl}ethyl]-1-(1-chloro-1-ethoxycarbonylmethyl)-2-azetidinone] (0.8 g) was dissolved indimethylformamide. To the solution was added 0.21 ml of triethylamine at-20° C., and the mixture was stirred at -20° to 0° C. for 1 hour. After10 ml of ethyl acetate was added to the reaction mixture, the mixturewas washed and an organic layer was collected by separation. After theorganic layer was dried, the solvent was removed. The residue waspurified by silica gel column chromatography (solvent; ethylacet-ate:n-hexane=1:5) to obtain 0.20 g of ethyl(5R,6S,7S)-7-[(R)-1-tert-butyldimethylsilyloxyethyl]-5-methyl-4,8-dioxo-1-aza-3-thia-bicyclo[4.2.0]octan-2-carboxylate.

IR (film) cm⁻¹ : 1779, 1745, 1690.

Mass (m/z): 486 (M⁺ -15), 344 (M⁺ -57).

NMR (CDCl₃) δ: 0.08 (s, 3H), 0.10 (s, 3H), 0.87 (s, 9H), 1.20 (d, 3H,J=6.4 Hz), 1.23 (d, 3H, J=6.8 Hz), 2.92 (dd, 1H, J=4.6 Hz, 3.0 Hz), 3.56(quintet, 1H, J=6.8 Hz), 4.1 to 4.3 (m, 1H), 4.29 (q, 2H, J=7.2 Hz),4.54 (dd, 1H, J=3.0 Hz), 5.79 (s, 1H).

(4) In 1 ml of toluene were dissolved 20 mg of the product obtainedabove and 16 mg of triphenylphosphine, to the solution was added 7 mg ofpotassium tert-butoxide at -40° C., and the mixture was stirred at -40°to -20° C. for 30 minutes. To the reaction mixture was added a solutionof 15 mg of diphenyl chlorophosphate dissolved in 0.5 ml of acetonitrileat the same temperature, and a temperature of the mixture was elevatedgradually up to 0° C. The reaction mixture was condensed, and theresidue was purified by thin layer chromatography (solvent; ethylacetate:n-hexane =1:4) to obtain 20 mg of ethyl(1R,5S,6S)-6-[(R)-1-tert-butyldimethylsilyloxyethyl]-2-diphenylphosphoryloxy-1-methylcarbapen-2-em-3-carboxylate(an oily product).

Mass (m/z): 601 (M⁺), 544 (M⁺ -57).

NMR(CDCl₃) δ: 0.06 (s, 6H), 0.87 (s, 9H), 1.1 to 1.3 (m, 9H), 3.23 (dd,1H, J=6.2 Hz, 3.0 Hz), 3.3 to 3.5 (m, 1H), 4.0 to 4.4 (m, 1H), 7.1 to7.4 (m, 10H).

Example 2

(1) The corresponding compound was treated in the same manner as inExample 1 (2) to obtain(3S,4S)-3-[(R)-1-tert-butyldimethylsilyloxyethyl]-4-[(1R)-1-{2,2-bis(ethoxycarbonyl)ethylthiocarbonyl}ethyl]-1-(1-hydroxy-1-p-nitrobenzyloxycarbonylmethyl)-2-azetidinone.

NMR(CDCl₃) δ: 0.0 to 0.10 (m, 6H), 0.86 (s, 9H), 1.1 to 1.3 (m, 12H),2.9 to 3.1 (m, 2H), 3.3 to 3.5 (m, 2H), 3.5 to 3.7 (m, 1H), 4.0 to 4.5(m, 7H), 5.3 to 5.6 (m, 3H), 7.5 to 7.6 (m, 2H), 8.2 to 8.3 (m, 2H).

(2) The product obtained above was treated in the same manner as inExample 1 (3) to obtain p-nitrobenzyl(5R,6S,7S)-7-[(R)-1-tert-butyldimethylsilyloxyethyl]-5-methyl-4,8-dioxo-1-aza-3-thia-bicyclo[4.2.0]octan-2-carboxylate.

IR (film) cm⁻¹ : 1786, 1742, 1682.

Mass (m/z): 451 (M⁺ -57).

NMR(CDCl₃) δ: 0.05 (s, 3H), 0.07 (s, 3H), 0.86 (s, 9H), 1.20 (d, 3H,J=6.2 Hz), 1.22 (d, 3H, J=6.7 Hz), 2.95 (dd, 1H, J=4.6 Hz, 3.0 Hz), 3.49(quintet, 3H, J=6.7 Hz), 4.0 to 4.3 (m, 2H), 4.55 (dd, 1H, J=7.1 Hz, 3.0Hz), 5.31 and 5.37 (ABq, 2H, J=13.1 Hz), 5.90 (s, 1H), 7.53 (d, 2H,J=8.8 Hz), 8.26 (d, 2H, J=8.8 Hz).

(3) The product obtained above was treated in the same manner as inExample 1 (4) to obtain p-nitrobenzyl (1R,5S,6S)-6-[(R)-1-tert-butyldimethylsilyloxyethyl]-2-diphenylphosphoryloxy-1-methylcarbapen-2-em-3-carboxylate.

NMR(CDCl₃) δ: 0.06 to 0.07 (m, 6H), 0.87 (s, 9H), 1.2 to 1.3 (m, 6H),3.27 (dd, 1H, J=5.6 Hz, 3.0 Hz), 3.3 to 3.6 (m, 1H), 4.1 to 4.3 (m, 2H),5.23 and 5.34 (ABq, 2H, J=13.8 Hz), 7.0 to 7.6 (m, 10H), 7.55 (d, 2H,J=8.8 Hz), 8.13 (d, 2H, J=8.8 Hz).

Example 3

(1) In dichloromethane were dissolved 1.4 g of(3S,4S)-3-[(R)-1-tert-butyldimethylsilyloxyethyl]-4-[(1R)-1-{2,2-bis(ethoxycarbonyl)ethylthiocarbonyl}ethyl]-2-azetidinoneand 0.64 g of pivaloyloxymethyloxalyl chloride, to the solution wereadded 0.34 ml of 2,6-lutidine and 10 mg of N, N-dimethylaminopyridineunder ice cooling, and the mixture was stirred at the same temperaturefor 30 minutes. To the reaction mixture were further added 0.64 g of(3S,4S)-3-[(R)-1-tert-butyldimethylsilyloxyethyl]-4-[(1R)-1-{2,2-bis(ethoxycarbonyl)ethylthiocarbonyl}ethyl]-2-azetidinoneand 0.34 ml of 2,6-lutidine, and the mixture was stirred for 30 minutes.The reaction mixture was poured into 100 ml of a 0.1M phosphate buffer(pH 7) and extracted with dichloromethane. After the extract was washedand dried, the solvent was removed under reduced pressure. The residuewas purified by silica gel column chromatography (solvent; ethylacetate:n-hexane=1:4) to obtain 1.72 g of(3S,4S)-3-[(R)-1-tert-butyldimethylsilyloxyethyl]-4-[(1R)-1-{2,2-bis(ethoxycarbonyl)ethylthiocarbonyl}ethyl]-1-pivaloyloxymethyloxyoxalyl-2-azetidinone.

IR (KBr) cm⁻¹ : 1809, 1752, 1732, 1701.

Mass (m/z): 618 (M⁺ -57).

NMR(CDCl₃) δ: 0.00 (s, 3H), 0.06 (s, 3H), 0.83 (S, 9H), 1.17 (d, 3H,J=6.4 Hz), 1.23 (s, 9H), 1.28 (t, 6H, J=7.0 Hz), 1.29 (d, 3H, J=7.0 Hz),3.2 to 3.6 (m, 5H), 4.2 to 4.4 (m, 1H), 4.25 (q, 4H, J=7.0 Hz), 4.4 to4.5 (m 1H), 5.90 (s, 2H).

(2) In a mixed solution of 10 ml of acetic acid and 10 ml ofdichloromethane was dissolved 1.7 g of the product obtained above, tothe solution was added 5 g of zinc under ice cooling, and the mixturewas stirred for 30 minutes. Insolubles were removed by filtration usingcelite, and the filtrate was removed under reduced pressure. The residuewas extracted with dichloromethane. After the extract was washed anddried, the solvent was removed under reduced pressure. The residue waspurified by silica gel column chromatography (solvent; ethylacetate:n-hexane=1:3) to obtain 1.52 g of(3S,4S)-3-[(R)-1-tert-butyldimethylsilyloxyethyl]-4-[(1R)-1-{2,2-bis(ethoxycarbonyl)ethylthiocarbonyl}ethyl]-1-[1-hydroxy-1-(pivaloyloxymethyloxycarbonyl)methyl]-2-azetidinone.

IR (KBr) cm⁻¹ : 3460, 1754, 1692.

Mass (m/z): 620 (M⁺ -57).

NMR (CDCl₃) δ: 0.08 (s, 6H), 0.88 (s, 9H), 1.22 (s, 9H), 1.1 to 1.4 (m,18H), 2.9 to 3.1 (m, 2H), 3.38 (dd, 1H, J=2.4 Hz, 7.4 Hz), 3.61 (t, 1H,J=7.1 Hz), 4.0 to 4.3 (m, 7H), 4.43 (d, 1H, J=8.8 Hz), 5.30+5.52 (d+d,1H, J=8.8 Hz), 5.7 to 5.9 (m, 2H).

(3) The product obtained above was treated in the same manner as inExample 1 (3) to obtain pivaloyloxymethyl(5R,6S,7R)-[(R)-1-tert-butyldimethylsilyloxyethyl]-5-methyl-4,8-dioxo-1-aza-3-thia-bicyclo[4.2.0]octan-2-carboxylate.

IR (KBr) cm⁻¹ : 1765, 1691.

Mass (m/z): 472 (M⁺ -15), 430 (M⁺ -57).

NMR (CDCl₃) δ: 0.06 (s, 3H), 0.88 (s, 3H), 0.87 (s, 9H), 1.21 (s, 9H),1.1 to 1.3 (m, 6H), 2.9 to 3.0 (m, 1H), 3.4 to 3.6 (m, 1H), 4.1 to 4.3(m, 1H), 4.5 to 4.6 (m, 1H), 5.81 (d, 1H, J=5.2 Hz), 5.83 (s, 1H), 5.91(d, 1H, J=5.2 Hz).

(4) The product obtained above was treated in the same manner as inExample 1 (4) to obtain pivaloyloxymethyl(1R,5S,6S)-6-[(R)-1-tert-butyldimethylsilyloxyethyl]-2-diphenylphosphoryloxy-1-methylcarbapen-2-em-3-carboxylate.

Mass (m/z): 687 (M⁺), 630 (M⁺ -57).

NMR (CDCl₃) δ: 0.06 (s, 6H), 0.86 (s, 9H), 1.1 to 1.3 (m, 15H), 3.2 to3.3 (m, 1H), 3.3 to 3.6 (m, 1H), 4.1 to 4.3 (m, 2H), 5.79 (d, 2H, J=1.4Hz), 7.2 to 7.4 (m, 10H).

Example 4

(1) The corresponding compound was treated in the same manner as inExample 3 (1) to obtain(3S,4S)-3-[(R)-1-tert-butyldimethylsilyloxyethyl]-4-[(1R)-1-{2,2-bis(ethoxycarbonyl)ethylthiocarbonyl}ethyl]-1-isobutyryloxymethyloxyoxalyl-2-azetidinone.

IR (film) cm⁻¹ : 1810, 1753, 1737, 1705.

Mass (m/z): 604 (M⁺ -57).

NMR (CDCl₃) δ: 0.07 (s, 3H), 0.58 (s, 3H), 0.83 (s, 9H), 1.1 to 1.4 (m,18H), 2.5 to 2.8 (m, 1H), 3.2 to 3.7 (m, 5H), 4.1 to 4.5 (m, 6H), 5.90(s, 2).

(2) The product obtained above was treated in the same manner as inExample 3 (2) to obtain(3S,4S)-3-[(R)-1-tert-butyldimethylsilyloxyethyl]-4-[(1R)-1-{2,2-bis(ethoxycarbonyl)ethylthiocarbonyl}ethyl]-1-[1-hydroxy-1-(isobutyryloxymethyloxycarbonyl)methyl]-2-azetidinone.

IR (KBr) cm⁻¹ : 3437, 1754, 1685.

Mass (m/z): 606 (M⁺ -57).

NMR (CDCl₃) δ: 0.08 (s, 6H), 0.88 (s, 9H), 1.1 to 1.4 (m, 18H), 2.5 to2.7 (m, 1H), 2.9 to 3.2 (m, 2H), 3.3 to 3.5 (m, 2H), 3.5 to 3.7 (m, 1H),4.0 to 4.5 (m, 7H), 5.3 to 5.6 (m, 1H), 5.7 to 6.0 (m, 2H).

(3) The product obtained above was treated in the same manner as inExample 1 (3) to obtain isobutyryloxymethyl(5R,6S,7S)-7-[(R)-1-tert-butyldimethylsilyloxyethyl]-5-methyl-4,8-dioxo-1-aza-3-thia-bicyclo[4.2.0]octan-2-carboxylate.

IR (KBr) cm⁻¹ : 1766, 1691, 1471.

Mass (m/z): 416 (M⁺ -57).

NMR (CDCl₃) δ: 0.06 (s, 3H), 0.08 (s, 3H), 0.87 (s, 9H), 1.1 to 1.3 (m,12H), 2.61 (m, 1H), 2.93 (dd, 1H, J=3.0 Hz, 4.8 Hz), 4.23 (m, 1H), 4.55(dd, 1H, J=2.9 Hz, 7.2 Hz), 5.82 (d, 1H, J=5.5 Hz), 5.83 (s, 1H), 5.90(d, 1H, J=5.5 Hz).

(4) The product obtained above was treated in the same manner as inExample 1 (4) to obtain isobutyryloxymethyl(1R,5S,6S)-6-[(R)-1-tert-butyldimethylsilyloxyethyl]-2-diphenylphosphoryloxy-1-methylcarbapen-2-em-3-carboxylate.

IR (film) cm⁻¹ : 1780, 1762, 1490.

Mass (m/z): 658 (M⁺ -15), 616 (M⁺ -57).

NMR (CDCl₃) δ: 0.06 (s, 6H), 0.87 (s, 9H), 1.1 to 1.3 (m, 12H), 2.55 (m,1H), 3.23 (dd, 1H, J=2.9 Hz, 6.2 Hz), 3.44 (m, 1H), 4.0 to 4.6 (m, 1H),7.2 to 7.5 (m, 10H).

Example 5

(1) The corresponding compound was treated in the same manner as inExample 1 (2) to obtain(3S,4S)-3-[(R)-1-tert-butyldimethylsilyloxyethyl]-4-[(1R)-2-{2,2-bis(ethoxycarbonyl)ethylthiocarbonyl}ethyl]-1-(1-hydroxy-1-allyloxycarbonylmethyl)-2-azetidinone.

NMR (CDCl₃) δ: 0.0 to 0.10 (m, 6H), 0.86 (s, 9H), 1.1 to 1.3 (m, 12H),2.9 to 3.1 (m, 2H), 3.3 to 3.4 (m, 2H), 3.5 to 3.7 (m, 1H), 4.0 to 4.5(m, 7H), 4.6 to 4.8 (m, 2H), 5.2 to 5.6 (m, 3H), 5.9 to 6.1 (m, 1H).

(2) The product obtained above was treated in the same manner as inExample 1 (3) to obtain allyl(5R,6S,7S)-7-[(R)-1-tert-butyldimethylsilyloxyethyl]-5-methyl-4,8-dioxo-1-aza-3-thia-bicyclo[4.2.0]octan-2-carboxylate.

IR (film) cm⁻¹ : 1779, 1745, 1690.

Mass (m/z): 356 (M⁺ -57).

NMR (CDCl₃) δ: 0.63 (s, 3H), 0.78 (s, 3H), 0.87 (s, 9H), 1.21 (d, 3H,J=6.2 Hz), 1.23 (d, 3H, J=6.7 Hz), 2.93 (dd, 1H, J=4.7, 2.9 Hz), 3.55(quintet, 1H, J=6.7 Hz), 4.1 to 4.3 (m, 1H), 4.55 (dd, 1H, J=7.2, 2.9Hz), 4.6 to 4.8 (m, 2H), 5.3 to 5.5 (m, 2H), 5.84 (s, 1H), 5.8 to 6.0(m, 1H).

Example 6

(1) In 300 ml of tetrahydrofuran was suspended 4.5 g of(4R)-4-hydroxy-2-pyrrolidone, 23.4 g of triphenylphosphine was addedthereto, and the mixture was stirred for 10 minutes. Subsequently, 14 mlof diethyl azodicarboxylate was added dropwise to the reaction mixtureat -10° C., and the mixture was stirred at the same temperature for 10minutes. After 6.3 ml of thioacetic acid was added dropwise to thereaction mixture at -10° C. or lower, the mixture was stirred at thesame temperature for 2 hours and the solvent was removed. The residuewas crystallized from diisopropyl ether. After the crystals were removedby filtration, the filtrate was condensed under reduced pressure. Theresidue was purified by silica gel column chromatography (solvent;chloroform:ethanol=98:2) to obtain 3.8 g of(4S)-4-acetylthio-2-pyrrolidone as an oily product.

NMR (CDCl₃) δ: 2.29 (dd, 1H), 2.35 (s, 3H), 2.81 (dd, 1H), 3.31 (dd,1H), 3.88 (dd, 1H), 4.10 to 4.23 (m, 1H), 7.02 to 7.17 (b, 1H).

(2) After a mixture of 4.8 g of the product obtained above, 100 ml oftoluene and 6.1 g of Lawesson's reagent (i.e.2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetan-2,4-disulfide) wasrefluxed under heating for 15 minutes, the solvent was removed. Theresidue was purified by silica gel column chromatography (solvent;chloroform:ethyl acetate=5:5) to obtain 3.6 g of(4S)-acetylthiopyrrolidin-2-thione as colorless needle crystal.

m.p.: 91° to 92° C.

[α]_(D) ²⁰ -57.5° (c=1, methanol ).

(3) A mixture of 3.6 g of the product obtained above and 36 ml of a 16%ammonia-methanol solution was stirred under ice cooling for 30 minutes.After the solvent was removed from the reaction mixture, 36 ml oftoluene was added to the residue and the mixture was condensed to obtain2.7 g of (4S)-4-mercaptopyrrolidin-2-thione as a crude product. Thisproduct was used without purification in the next step.

(4) In 1 ml of acetonitrile was dissolved 20 mg of pivaloyloxymethyl(1R,5S,6S)-6-[(R)-1-tert-butyldimethylsilyloxyethyl]-2-diphenylphosphoryloxy-1-methylcarbapen-2-em-3-carboxylate,4.3 mg of (4S)-4-mercaptopyrrolidin-2-thione obtained in the above (3)and 4.1 mg of N,N-diisopropylethylamine were added thereto undernitrogen gas at -20° C., and the mixture was stirred for 2 hours whilegradually elevating a temperature thereof to 0° C. The reaction mixturewas poured into a 0.1M phosphate buffer (pH 7) and extracted with ethylacetate. After the extract was washed and dried, the solvent was removedunder reduced pressure. The residue was purified by thin layerchromatography (solvent; ethyl acetate:n-hexane=5:5) to obtain 7 mg ofpivaloyloxymethyl (1R, 5S, 6S)-6-[(R)-1-tert-butyldimethylsilyloxyethyl]-2-[(4R)-pyrrolidin-2-thion-4-ylthio]-1-methylcarbapen-2-em-3-carboxylate ascolorless crystal.

m.p.: 143° C.

Mass (m/z): 536 (M⁺ -34).

Example 7

(1) In 10 ml of toluene were dissolved 500 mg of isobutyryloxymethyl(5R,6S,7S)-7-[(R)-1-tert-butyldimethylsilyloxymethyl]-5-methyl-4,8-diozo-1-aza-3-thia-bicyclo-[4.2.0]octan-2-carboxylateand 277 mg of triphenylphosphine, 130 mg of potassium tert-butoxide wasadded thereto under nitrogen gas at -40° C. while stirring, and themixture was stirred at the same temperature for 50 minutes. To thereaction mixture was added dropwise 10 ml of acetonitrile solutioncontaining 312 mg of diphenyl chlorophosphate at -40° C., and themixture was stirred for 40 minutes. To the reaction mixture were added155 mg of (4S)-4-mercaptopyrrolidin-2-thione and 148 mg ofdiisopropylethylamine, and the mixture was stirred at -20° C. for 80minutes, and then at -5° C. for 1.5 hours. The reaction mixture waspoured into a 0.1M phosphate buffer (pH 7.0) and extracted with ethylacetate. After the extract was washed and dried, the solvent was removedunder reduced pressure. The residue was purified by silica gel columnchromatography (solvent; n-hexane:ethyl acetate:chloroform =5:5:1) toobtain 248 mg of isobutyryloxymethyl (1R,5S,6S)-6-[(R)-1-tert-butyldimethylsilyloxyethyl]-2-[(4R)-pyrrolidin-2-thion-4-ylthio]-1-methylcarbapen-2-em-3-carboxylate.

m.p.: 142° C. (decomposed).

IR (KBr) cm⁻¹ : 3347, 1771, 1590, 1537.

(2) In 0.2 ml of tetrahydrofuran was dissolved 10 mg of the productobtained above, 0.006 ml of acetic acid and 0.072 ml of tetrahydrofuransolution containing 1M of tetrabutylammonium fluoride were addedthereto, and the mixture was stirred at room temperature for 3 days.After the reaction mixture was diluted with ethyl acetate and thenwashed, an organic layer was collected by separation. After the organiclayer was dried, the solvent was condensed under reduced pressure. Theresidue was purified by silica gel column chromatography (solvent; ethylacetate) to obtain 5 mg of isobutyryloxymethyl(1R,5S,6S)-2-[(4R)-pyrrolidine-2-thion-4-ylthio]-6-[(1R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylateas colorless needle crystal.

m.p.: 158° to 159° C.

Reference example 1

(1) A mixture of 80 g of diethyl malonate, 30 g of paraformaldehyde, 5 gof potassium acetate, 5 g of copper (II) acetate monohydrate and 200 mlof acetic acid was heated at 90° to 100° C. for 2 hours. Acetic acid wasremoved from the reaction mixture under reduced pressure, and theresidue was evaporated under reduced pressure to obtain 44 g ofbis(ethoxycarbonyl)ethylene.

b.p.: 90° to 93° C. (1.3 mmHg).

(2) The product obtained above was added dropwise to 500 ml oftetrahydrofuran solution containing 22 g of thioacetic acid and 500 mgof potassium thioacetate under ice cooling and stirring. The solvent wasremoved from the reaction mixture. After diethyl ether was added to theresidue, the mixture was washed and dried and the solvent was removed.To the residue was added 2N hydrochloric acid-ethanol, and the mixturewas stirred at room temperature for 14 hours. The solvent was removedfrom the reaction mixture, and the residue was evaporated under reducedpressure to obtain 18.3 g of diethyl mercaptomethylmalonate.

b.p.: 78° to 82° C. (1 mmHg).

¹ H-NMR (CDCl₃) δ1.29 (t, 6H, J=7.1 Hz), 1.73 (t, 1H, J=8.9 Hz), 3.00(dd, 2H, J=8.9 Hz, 7.3 Hz), 3.57 (t, 1H, J=7.3 Hz), 4.23 (q, 4H, J=7.1Hz).

Reference example 2

(1) To 425 g of isobutyryl chloride were added 850 mg of zinc chlorideand 119 g of paraformaldehyde, and the mixture was heated at 90° to 100°C. for 8 hours. The reaction mixture was evaporated (three times), andthe fractions having a boiling point of 120° to 130° C. were collectedto obtain 311 g of chloromethyl isobutyrate.

(2) In 4 l of acetone were dissolved 3.53 kg of monobenzyl oxalate.tetran-butyl ammonium salt and 1.13 kg of chloromethyl isobutyrate preparedin the above (1), and the solution was stirred overnight. Acetone wasremoved from the reaction mixture under reduced pressure, and theresidue was dissolved in ethyl acetate. After the solution was washedand dried, the solvent was removed to obtain 2.22 kg ofbenzylisobutyloxymethyl oxalate (a pale yellowish oily product).

IR (film) cm⁻¹ : 1754.

Mass (m/z): 290 (M⁺).

(3) In 200 ml of ethyl acetate was dissolved 28 g of the productobtained above, 5 g of 10% palladium-carbon was added thereto, and themixture was subjected to catalytic reduction under pressure for 8 hours.The catalyst was removed by filtration from the reaction mixture, andthe filtrate was condensed to obtain 18 g of monoisobutyryloxymethyloxalate (a colorless oily product).

IR (film) cm⁻¹ : 1756.

Mass (m/z): 190 (M⁺).

(4) In 200 ml of methylene chloride was dissolved 26 g of the productobtained above, to the solution was added 17 g of oxalyl chloride, andthe mixture was stirred at room temperature for 3 hours. The reactionmixture was condensed, and 50 ml of benzene was added to the residue andremoved under reduced pressure (three times). Then, the residue wasevaporated to obtain 15 g of oxalic acid chloride isobutyryloxymethylester (a colorless oily product).

b.p.: 78° to 80° C. (1 mmHg).

IR (film) cm⁻¹ : 1768.

Mass (m/z): 208 (M⁺).

According to the process of the present invention, by using the novelcompound 1-aza-3-thia-bicycloalkane compound (II) as a startingcompound, the β-lactam derivative (I) useful as a synthetic intermediateof carbapenem (or penem) type and cephem type antibacterial agents andthe compound (IV) useful as an antibacterial agent can be prepared bysimple and easy operations with good efficiency.

For example, the process of the present invention has a characteristicthat base treatment in the presence of the above desulfurizing agent andactive esterification of the compound (II), and subsequent condensationreaction with the mercaptan compound (III) can be carried out in thesame reactor.

In a conventional process described in Japanese Provisional PatentPublication No. 123182/1982, when the compound (IV) in which the grouprepresented by R² is an easily eliminatable ester residue such asisobutyryloxymethyl group is prepared, if a corresponding startingcompound in which R² is such an ester residue is used, there is aproblem that said ester residue is eliminated during reaction operation.However, in the process of the present invention, the ester residue isnot eliminated during reaction operation, so that the desired compound(IV) can be obtained with good efficiency.

Further, the process of the present invention also has a characteristicthat the process proceeds not through a diazo compound type intermediateused in the process described in Japanese Provisional Patent PublicationNo. 123182/1982, so that the process can be carried out without using anazide compound such as sulfonylazide which should be handled carefully.

Furthermore, the carbapenem compound (IV-c) derived from the β-lactamderivative (I) of the present invention or a pharmacologically orpharmaceutically acceptable salt thereof is a novel compound havingvarious extremely excellent characteristics as an antibacterial agent.

For example, the compound (IV-c) or a pharmacologically acceptable saltthereof has an excellent antibacterial activity to variousmicroorganisms including gram-positive bacteria and gram-negativebacteria such as Escherichia, Staphylococcus and Pseudomonas, and alsohas a high antibacterial activity to pathogenic clinically separatedstrains. Thus, the compound (IV-c) or a pharmacologically acceptablesalt thereof exhibits an excellent therapeutic effect on infectiousdiseases.

The compound (IV-c) has stronger antibacterial activities toStaphylococcus aureus, Staphylococcus epidermidis, Escherichia coli,Proteus vulgaris and Pseudomonas aeruginosa, 2-fold to 4-fold or morethan those of the compound in which a substituent at 2-position is2-oxopyrrolidin-4-ylthio group described in Japanese Provisional PatentPublication No. 49783/1990.

Further, the compound (IV-c) or a pharmacologically acceptable saltthereof has an excellent characteristic of exhibiting higher stabilityto dehydropeptidase I by using 2-thioxopyrrolidin-4-ylthio group at2-position of a 1-methylcarbapenem skeleton.

For example, the compound (IV-c) exhibits more excellent stability todehydropeptidase I, by 2-fold or more as compared with the compounddescribed in the above Japanese Provisional Patent Publication No.49783/1990.

Also, the compound (IV-c) or a pharmacologically acceptable salt thereofhas characteristics of having high oral absorption property andexhibiting a high therapeutic effect.

For example, when the compound (IV-c) is orally administered to a mouseinfected with Staphylococcus aureus, a higher therapeutic effect by2-fold to 8-fold is exhibited as compared with the case when thecompound described in the above Japanese Provisional Patent PublicationNo. 49783/1990 is orally administered.

Further, the compound (IV-c) or a pharmacologically acceptable saltthereof has high transition property to bile, and therefore isparticularly available for biliary infections.

Also, the compound (IV-c) or a pharmacologically acceptable salt thereofhas low toxicity and has high safety as a medicine.

We claim:
 1. A 1-aza-3-thia-bicycloalkane compound represented by theformula: ##STR16## wherein R¹ represents a hydroxy-substituted loweralkyl group which may be protected or an amino group which may beprotected; R² represents hydrogen atom or an ester residue; X representsa methylene, a methylene group substituted by a lower alkyl group,sulfur atom or a group represented by the formula: --A--CH₂ -- where Arepresents sulfur atom, oxygen atom or methylene group;or a saltthereof.
 2. The compound according to claim 1, wherein R¹ is a1-hydroxyethyl group which may be protected, and X is ethylidene group.3. The compound according to claim 1, wherein R¹ is an amino group whichmay be protected, and X is a group represented by the formula: --S--CH₂--, --O--CH₂ -- or --CH₂ CH₂ --.
 4. A 1-aza-3-thia-bicycloalkanecompound represented by the formula: ##STR17## wherein: R¹ representsahydroxy-substituted lower alkyl group which may be protected by a groupselected from group consisting of a lower alkoxycarbonyl group, ahalogeno lower alkoxycarbonyl group, a phenyl lower alkyl group whichmay be substituted by a nitro group or a lower alkoxy group, a tri-loweralkylsilyl group, and a phenyl lower alkoxycarbonyl group which may besubstituted by a nitro group or a lower alkoxy group, or an amino groupwhich may be protected by a group selected from the group consisting ofa lower alkanoyl group, a lower alkoxycarbonyl group, a benzoyl group, abenzenesulfonyl group, a phenyl lower alkoxycarbonyl group, a tri-loweralkylsilyl group and a trityl group: R² represents a hydrogen atom, agroup of the formula

    --O--OCOR, --O--OCO.sub.2 R or --O--O--R

wherein O represents a lower alkylene group, and R represents a loweralkyl group, a cycloalkyl group of 3 to 8 carbon atoms, a lower alkenoylgroup, a lower alkoxy lower alkyl group, or a lower alkanoyloxy loweralkyl group,a lower alkyl group, a lower alkenyl group, a halogeno loweralkyl group, a nitrobenzyl group or a lower alkoxybenzhydryl group; andX represents a methylene group substituted by a lower alkyl group;or analkali metal salt thereof.
 5. The compound according to claim 4, whereinR¹ is a 1-hydroxyethyl group which may be protected by a group selectedfrom group consisting of a lower alkoxycarbonyl group, a halogeno loweralkoxycarbonyl group, a phenyl lower alkyl group which may besubstituted by a nitro group or a lower alkoxy group, a tri-loweralkylsilyl group, and a phenyl lower alkoxycarbonyl group which may besubstituted by a nitro group or a lower alkoxy group and X is ethylidenegroup.
 6. The compound according to claim 4, wherein R¹ is an aminogroup which may be protected by a group selected from the groupconsisting of a lower alkanoyl group, a lower alkoxycarbonyl group, abenzoyl group, a benezenesulfonyl group, a phenyl lower alkoxycarbonylgroup, a tri-lower alkylsilyl group and a trityl group, and X is a grouprepresented by the formula: --S--CH₂ --, --O--CH₂ -- or --CH₂ CH₂ --. 7.The compound according to claim 4, wherein:R¹ is a 1-hydroxyethyl groupwhich may be protected by a tri-lower alkylsiliyl group, X is anethylidene group, R² is a lower alkyl group, a lower alkenyl group anitrobenzyl group or a group represented by the formula: --Q--OCOR,wherein Q is a lower alkylene group and R is a lower alkyl group.
 8. Thecompound according to claim 4, wherein the phenyl lower alkyl group is abenzyl group and the phenyl lower alkoxycarbonyl group is abenzyloxycarbonyl group.
 9. The compound according to claim 4, wherein Xis a group of the formula: ##STR18##
 10. The compound according to claim5, wherein X is a group of the formula: ##STR19##
 11. The compoundaccording to claim 7, wherein X is a group of the formula: ##STR20##